Brain fluid ion concentration modification for treating neurological disorders

ABSTRACT

Epilepsy and other neurological disorders that are affected by the electrical potential difference between intracellular fluid and extra-cellular fluid and therefore the cell membrane potentials, and therefore the thresholds for the communication between brain cells can be controlled by re-circulating extra-cellular brain fluid after the fluid has been treated to alter its ion concentrations. A computer-controlled pump can precisely control the extraction and delivery of brain fluid after the ion concentration of the fluid is appropriately adjusted, e.g. guided by the Goldmann equation. Well-known techniques for modifying ion concentrations can be used to raise or lower ion concentrations as needed.

[0001] This application is a continuation application of U.S. Ser. No.09/561,550, filed Apr. 28, 2000.

FIELD OF THE INVENTION

[0002] This invention relates to methods of treating medical disorders.In particular, this invention relates to a method of treating the causeof epilepsy, which is rooted in the basic concepts described by theGoldman equation. This equation describes the relation between the cellrest membrane potential and the concentration of ions inside and outsidethe cells in e.g nervous and muscle tissue. This implies that cellexcitability can be modified and therefore the physiologicalinter-connectivity between cells. This interconnectivity is a majorfactor in the generation of e.g. epilepsy. The key concept of thisinvention is that if cell rest membrane electrical potentials aremodified, epilepsy, and perhaps other neurological disorders might beeffectively controlled.

BACKGROUND OF THE INVENTION

[0003] Epilepsy is a debilitating neurological disorder. Functionalcontrol of many or all body functions can be lost and further permanentbrain damage results from each generalized epileptic attack.

[0004] It is known that an epileptic seizure is manifested by anuncontrolled propagation of nerve impulses throughout the nerve cells incertain, areas of the brain. The nerve impulses of an epileptic seizureare characterized by many synchronized discharges, which may involve thewhole brain. As a consequence the control of many body functions islost. During epileptic seizures, the normal physiologicalinterconnectivity between brain cells is greatly altered, resulting in asynchronized highly pathological brain activity.

[0005] It is well known that the normal, electrical, rest membranepotential difference between intra-cellular fluid (fluid enclosed by thecell membrane) of brain cells and the extra-cellular brain fluid (fluidoutside the membrane ) is about −0.07 volts (−70 millivolts or mV.) Theintra-cellular brain fluid is at a more negative potential than theextracellular fluid potential. If this potential becomes more negative(cells are hyperpolarized), the likelihood of an epileptic seizure isdecreased. In the field of biophysics, the well known Goldmann equationdescribes how the membrane potential depends on the concentrations ofions in the intra- or extra-cellular medium. Consequently this equationdescribes how changes in the extra-cellular ion concentrations willresult in a hyper-polarization of brain cells which will result insuppression of epileptic seizures.

SUMMARY OF THE INVENTION

[0006] A method of treating epilepsy whereby seizures can be suppressedor prevented by using extra-cellular fluid (in the central nervoussystem, cerebral spinal fluid or “CSF”) that is extracted from thebrain, e.g from one of the brain ventricles. The extracted brain fluidis treated to change the concentration of ions in the fluid in such away that cells surrounded by this modified fluid will be hyper-orhypo-polarized which is quantitatively predicted by the Goldmannequation. The ion-adjusted fluid is re-injected into the brain into aspecific brain structure, which may contain the brain cells thatgenerate the epileptic seizure (hyper-polarization needed) or in a brainstructure that modulates the epileptic region (hyper-polarization neededfor suppressing structures and hypo-polarization needed for activatingstructures). The increased negative potential difference(hyper-polarization) between the intra and extra-cellular fluid in theepilepsy-generating brain structure increases the potential differencethat the nerve cells must overcome to be involved in the generation ofan epileptic seizure. In effect, the invention includes modulating theinterconnectivity of nerve cells by modulating the rest membraneelectrical potential.

BRIEF DESCRIPTION OF THE DRAWINGS

[0007]FIG. 1 shows the steps of the method contemplated herein.

[0008]FIG. 2 shows a simplified block diagram of an apparatus that couldperform the method disclosed and claimed herein.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

[0009]FIG. 1 shows a simplified schematic block diagram for a mechanicalsystem for treating epilepsy and other neurological disorders bymodifying ion concentration in brain fluid. In FIG. 1, fluid from apatient's brain 10 (the fluid is not shown) is extracted from the brain(preferably from 1 of the brain ventricles) 10, by a pump 14.Extra-cellular fluid can be extracted by exerting a relatively negativepressure on a small-diameter flexible conduit (i.e. a catheter orcapillary tube 12) one end of which is coupled to the pump and whichprovides the negative pressure. The other end of the flexible conduit isinserted into the brain ventricle. Extra-cellular brain fluid is drawnthrough an appropriately-sized capillary tube or catheter 12 to the pump14, which in the preferred embodiment was a positive displacementcomputer-controlled pump 14.

[0010] In the preferred embodiment, the pump 14 (which may be computercontrolled) reads and executes stored program instructions that causethe pump to pump the extracted fluid according to the program and itsparameters. In many applications, ion-adjusted fluid will be pumped inan “open loop” fashion, i.e. according to some predetermined schedule inthe pump's stored program. Open-loop delivery methods can be based uponeither the volume of modified extra-cellular brain fluid to be deliveredper unit time or some other parameter.

[0011] The pump 14 forces extracted extra-cellular brain fluid throughan ion concentration adjustment mechanism 16. Ion concentrations in theextracted brain fluid are modified in the ion concentration adjustmentmechanism 16. The ion concentration of the fluid can be adjusted bymethodologies well known in the art including, but not limited to,appropriate ion exchange mechanisms; filtration, or chemical treatment.The ion concentration adjustment mechanism 16 changes the ionconcentration in brain fluid such that when the fluid is returned to thebrain, the brain fluid ion concentration, at least in localized regions,is modified. Output from the ion concentration adjustment mechanism 16is returned to the brain 10 through an appropriately sized capillarytube or catheter 18.

[0012] Procedural steps of the method 200 of the invention areillustrated in FIG. 2. CSF or extra-cellular brain fluid is extracted210 and the ion-concentration of the fluid is adjusted 220 using anappropriate methodology. Some techniques for modifying ion concentrationwould include filtering or various chemical treatment processes. Afterthe ion concentration is adjusted, the modified ion-content fluid isre-injected into the patient's brain 230.

[0013] At some point in the process, the flow rate of brain fluid fromand/or into the patient's brain is measured 240. While this step isshown in FIG. 2 as being after re-injection of the brain fluid 230,alternate methodologies would certainly include deleting this step inits entirety and simply letting the pump run “open loop” doing whateverthe program instructions dictate. Still other embodiments would includecalculating or measuring the extracted fluid 210 volume as well as thedelivered fluid volume. Inasmuch as brain fluid is incompressible, boththe extracted and re-injected or delivered fluid volumes should beequivalent, except for any fluid lost during the ion-concentrationadjustment.

[0014] Still other embodiments might measure the ion concentration inthe brain fluid and, depending upon the measured ion concentration,adjust the fluid delivery rate or the ionconcentration adjustment, orboth. In an optimum system, a closed-loop feedback system would includea system that measures ion concentration (or other electricalcharacteristic) and uses this information to control fluid extraction,delivery or ion content so as to achieve the optimum electricalpotential difference between the inside and outside of brain cells,imbalances of which might cause epilepsy or other neurologicaldisorders.

[0015] Various embodiments of the invention include localized deliveryof ion-modulated brain fluid as well as dispersed delivery mechanism,such as a leaky catheter. By replacing the brain fluid at a modified ionconcentration, it is possible to change the electrical potentialdifference between intra-cellular and extra-cellular brain fluid.

[0016] In the preferred embodiment, changing the electrical potentialdifference across the nerve cell membrane in the epilepsy generatingbrain structure can significantly affect the occurrence of epilepticseizures. Once a diagnosis of epilepsy is first made or the disease isestablished, changing the ion concentration in the extra-cellular fluidto increase the potential difference from −70 millivolts to −80 or moremillivolts will locally hyperpolarize the brain cells and therefore, cansubstantially inhibit seizures.

[0017] In one of the alternate embodiments, an electrical probe 20inserted into a localized region of the brain 10 might be read by thecomputer that controls the pump 14 so as to provide closed-loop feedbackso as to even more closely control ion concentrations and therefore moreclosely control epileptic seizures. A probe inserted into the brainfluid in the brain might measure the ion concentration by theconductivity or resistance of the fluid. In such an embodiment, it ispreferable to measure ion concentration after the ion-adjusted fluid hasbeen returned to the patient's brain. The modified resulting membranepotential can be calculated using the well-known Goldman equation. Inanother alternate embodiment, ion concentrations of extra-cellular fluidmight be adjusted according to measured electrical activity of nervecells in specific brain structures involved in the generation of theepileptic seizures. In such an embodiment, the electrical activity ofbrain cells, can be continuously adjusted by injecting more or lessmodified brain fluid in such a way to avoid seizures. Such a closed-loopsystem could be used to carefully control, in real time, the rate atwhich ion adjusted fluid is delivered to the brain or to change the ionconcentration changes effected by the ion concentration adjustmentmechanism 16. A control signal 22 from the computer-controlled pump 14might be used to change the ion concentration in fluid that is output tothe brain 10. In yet another embodiment, it might be possible to alterelectrical potential differences across cell membranes simply by addingor administering a predetermined liquid or other substance to brainfluid so as to change the electrical potential across brain cells.

[0018] Those skilled in the art will recognize that changing the ionconcentration of extracellular brain fluid could have other beneficialeffects in the treatment of other neurological disorders by adjustingthe degree of communication between brain cells. This degree ofcommunication depends on the level of the membrane potential.Hyper-polarized or inhibited cells increase the threshold for cellcommunication, while hypo-polarized or excited cells decrease thethreshold for cell communication. In instances where neurologicaldisorders can be controlled by modulating the communication betweenbrain cells the invention would find the applicability in treating theseother disorders.

1. A method for treating epilepsy and other neurological disorders ofthe brain comprising the steps of: a) extracting fluid from a braincavity of a patient; b) modifying ion concentrations of said fluid torender modulated ion-content fluid; c) returning the modulatedion-content fluid locally into the patient's brain.
 2. The method ofclaim 1 wherein said step c) of returning modulated ion-content fluidinto the patient's brain is further comprised of the step c) of:returning modulated ion-content fluid into the patient's brain into atleast one localized region of the patient's brain.
 3. The method ofclaim 1 wherein said step c) of returning modulated ion-content fluidinto the patient's brain is further comprised of the step of c) pumpingsaid modulated ion-content fluid into the patient's brain according to apredetermined schedule of flow rate
 4. The method of claim 1 whereinsaid method is further comprised of c): returning modulated ion-contentfluid into the patient's brain into a general region of the patient'sbrain.
 5. The method of claim 1 further comprised of the steps of: d)measuring ion concentration in said brain fluid after said modulatedion-content fluid, is returned to said patient's brain; e) adjusting thedelivery of said modulated ion-content fluid, based upon the measuredion concentration of step d).
 6. The method of claim 1 further comprisedof the steps of: d) calculating ion concentration in said brain fluid,using the Goldman equation; e) adjusting the delivery of said modulatedion-content fluid, based upon the calculated ion concentration of stepd).
 7. The method of claim 1 further comprised of the steps of: d)measuring the electrical conductivity of said brain fluid after saidmodulated ion-content fluid, is returned to said patient's brain; e)adjusting the delivery of said modulated ion-content fluid, based uponthe measured electrical conductivity of said brain fluid.
 8. The methodof claim 1 wherein delivery of said modulated ion-content fluid iscalculated using the Goldman equation.
 9. The method of claim 1 whereinthe modulated ion-content fluid returned to the brain produces a voltagedifferential between intra-cellular fluid and extra-cellular fluid,which may be modified to such a level that epileptic seizures arecontrolled.
 10. The method of claim 6 wherein said modulated ion-contentfluid is delivered to the patient's brain using closed-loop feedback.11. The method of claim 1 further comprised of the step of adjusting thedelivery of modulated ion-content fluid based upon the measuredelectrical activity of predetermined most likely epileptic brain cells.12. The method of claim 2 wherein said modulated ion-content fluid isreturned to the brain using a dispersed delivery system.
 13. The methodof claim 2 wherein said modulated ion-content fluid is returned to thebrain ventricle.
 14. The method of claim 1 wherein said modulatedion-content fluid is returned to the brain using a computer-controlledpump.
 15. The method of claim 1 wherein said modulated ion-content fluidis returned to the brain at a predetermined location by direct injectioninto a localized region.
 16. A method for treating epilepsy and otherneurological disorders of the brain comprising the steps of: a)diagnosing an epileptic condition in a patient; b) substantiallycontinuously extracting fluid from the brain of the patient; c)modifying ion concentrations of said fluid to render modulatedion-content fluid using a predetermined process; d) substantiallycontinuously pumping the modulated ion-content fluid back into alocalized region of the patient's brain; e) monitoring the ionconcentration of brain fluid proximate to the region where saidmodulated ion-content fluid is returned to the patient's brain.
 17. Asystem for controlling epileptic seizures comprising: a) diagnosing anepileptic condition; b) a brain fluid pumping mechanism, having aninput, coupled to a patient's brain for extracting brain fluid, andhaving an output; c) a fluid ion adjustment mechanism coupled to saidoutput of said brain fluid pumping mechanism, said fluid ion adjustmentmechanism having an output from which ion-adjusted fluid is produced; d)a catheter, having an input coupled to the output of said ion adjustmentmechanism and having an output inserted into a predetermined region of apatient's brain; whereby brain fluid is extracted from a patients brain,ion-concentration of said fluid are adjusted and said brain fluid isre-injected into said brain.